Copolymers of hydrophobic and hydrophilic segments that reduce protein adsorption

ABSTRACT

The present disclosure relates to compositions A composition comprising a polymerization product of an anionic polysaccharide, a diisocyanate, and a linker, wherein the linker comprises i) an ether group, an ester group, or a combination thereof and, ii) a chain extender comprising a hydroxyl group, a thiol group, an amine group, or a combination thereof. The disclosure further relates to medical devices comprising the aforementioned compositions, and to methods of using the compositions and devices. More particularly, the compositions, devices and methods described herein are useful for preventing protein adhesions in vivo, particularly the Vroman effect.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of ProvisionalApplication No. 61/544,260 filed on Oct. 6, 2011, and is a continuationof U.S. patent application Ser. No. 13/645,941, the contents of whichare herein incorporated by reference in their entirety.

TECHNICAL FIELD

The present disclosure provides copolymers and compositions comprisingthe same, which are useful for reducing or preventing protein absorptionin vivo, and more particularly, the Vroman effect.

BACKGROUND

The Vroman Effect is exhibited by protein adsorption to a surface byblood serum proteins. The highest mobility proteins generally arrivefirst and are later replaced by less motile proteins that have a higheraffinity for the surface. A typical example of this occurs whenfibrinogen displaces earlier adsorbed proteins on a biopolymer surfaceand is later replaced by high molecular weight kininogen. In surgicalapplications and wound healing, a generalized Vroman effect can beapplied to all cellular/prosthetic interactions, wherein a foreign bodyis identified by the denaturation of proteins that attach to the implantsurface, and thus label the implant as a foreign body and signal cellsto wall off or removed by phagocytosis an implant. Similarly, cellstraveling through the extracellular matrix of tissue proceed by layingdown proteins from which they derive locomotion. Thus, an implant thatprevents protein attachment prevents both labeling of an implant as aforeign body and colonization of the implant by fibrogenic cells andmicrobes.

Thus, controlling protein adsorption on implantable medical devices isimportant in controlling the foreign body response, the adverse form ofwhich is chronic inflammation. Chronic inflammation leads to fibroticencapsulation and the release of several factors that result inapoptosis and abundance of reactive oxygen species.

Biomaterials typically exhibit diverse protein adsorption, leading tomixed layers of partially denatured proteins. These surfaces containdifferent cell binding sites due to adsorption of proteins such asfibrinogen, immunoglobulin which results in attachment of inflammatorycells such as macrophages and neutrophils. When activated, these cellssecret a wide variety of pro-inflammatory and proliferative factors.Hydrophilic surfaces control these events, and absorb little or noprotein, primarily due to their dipole interactions with water.Unfortunately, hydrophilic substances generally possess poor volumestability and are susceptible to hydrolytic and enzymatic degradation.

Implants can generally be divided into two categories, those that areabsorbable, and those that are intended to be biostable. For thoseimplants that are bioabsorbable, it is important that the absorptionrate is sufficiently slow to minimize inflammatory response and localchanges in pH. Complete healing of a surgically altered site is widelybelieved to be about 6 months, if the patient has a normal healingresponse, for example adequate collagen production and blood supply. Incases where healing is compromised, a bioabsorbable implant may need toprovide mechanical integrity for multiple years, while avoiding aforeign body response.

Accordingly, there is a need for a composition useful for medicaldevices that prevents protein adsorption while possessing volumetricstability and durability in vivo for a desired period of time. Suchcompositions would be expected to mitigate the foreign body response invivo.

BRIEF SUMMARY

The present disclosure provides a composition comprising apolymerization product of an anionic polysaccharide, a diisocyanate, anda linker, wherein the linker comprises i) an ether group, an estergroup, or a combination thereof and, ii) a chain extender comprising ahydroxyl group, a thiol group, an amine group, or a combination thereof.In certain embodiments, the polymerization product comprises a copolymerof a prepolymer and the linker, wherein the prepolymer comprises acopolymer of the anionic polysaccharide and the diisocyanate. Theprepolymer comprises, in certain embodiments, at least one segmentrepresented by I[BABBAB]nI, wherein, independently for each occurrence,A represents a polysaccharide block, B represents a urethane or ureablock, I represents an isocyanate and n represents and integer rangingfrom 1 to 10,000. In certain embodiments, the linker comprises at leastone segment represented by ECE, wherein, independently for eachoccurrence, C represents an ether block, an ester block or a combinationthereof, and E represents a chain extender comprising a hydroxyl, athiol or an amine group. Thus, the polymerization product may compriseat least one segment represented by [BABBAB]_(n)BCB[BABBAB]_(n),wherein, independently for each occurrence, A represents apolysaccharide block, B represents a urea or urethane block, Crepresents an ether block, and ester block or a combination thereof, andn represents an integer ranging from 1 to 10,000.

In other embodiments, the polymerization product comprises a copolymerof a prepolymer and the anionic polysaccharide, wherein the prepolymercomprises a copolymer of the linker and the diisocyanate. In certainembodiments, the prepolymer comprises at least one segment representedby IBCBI, wherein C represents an ether block, an ester block, or acombination thereof. wherein the prepolymer comprises at least onesegment represented by IBCBI, and wherein C represents an ether block,an ester block, or a combination thereof. Thus, when combined with alinker represented by ECE, the polymerization product comprises at leastone segment represented by ABBCBBA, wherein independently for eachoccurrence, A represents a polysaccharide block, B represents a urea orurethane block, and C represents an ether block, an ester block, or acombination thereof.

The aforementioned polymerization products, in certain embodiments, thuscomprise a polymer of one or more polyanionic polysaccharides and one ormore non-absorbable ethers combined via urea or urethane links, whichassociate within the composition by hard segment bonding. Moreparticularly, disclosed is a biocompatible composition (e.g. for coatingor device) containing one or more polyanionic polysaccharides (e.g.hyaluronic acid, alginates, cellulose) combined with one or morehydrophilic non-absorbable ethers, the combination means comprising aurea or urethane link which associate within the composition by hardsegment bonding.

In certain embodiments, the copolymers described herein are capable ofreducing or preventing protein adsorption, and more particularly, theVroman effect, in viva More particularly, in certain embodiments, thecopolymers comprise hydrophobic and hydrophilic domains.

The disclosure also provides medical devices comprising a compositioncomprising a polymerization product of an anionic polysaccharide, adiisocyanate, and a linker, wherein the linker comprises i) an ethergroup, an ester group, or a combination thereof and, ii) a chainextender comprising a hydroxyl group, a thiol group, an amine group, ora combination thereof. The present disclosure further provides methodsof reducing protein adsorption using the aforementioned medical devicesin vivo.

The present disclosure further provides compositions comprisingcopolymers of hydrophilic domains and hydrophobic domains. In certainembodiments, the hydrophilic domains prevent protein adsorption, whilethe hydrophobic domains provide structural stability. The compositionsof the disclosure can be provided in the form of an adhesion preventioncomposition, e.g., in a coating, membrane, foam, film, or compositionsuitable for extrusion. For example, the compositions can be extrudedinto fibers and knitted or weaved into a fabric. In particularembodiments, the composition comprises a water insoluble polysaccharide,and is produced in the form of fibers or fabric. In certain embodiments,the composition may also be provided in a prepolymeric form and thenfurther copolymerized to form a device or coating for a device, forexample, a coating for a mesh, such as polypropylene mesh, orcopolymerized to form a film.

It is an object of the present disclosure to provide a polysaccharidepolymerized with urea or urethane links subsequently reacted with etheror ester groups wherein at least two polysaccharide groups are connectby urea or urethane links.

It is another object of the present disclosure to provide a substancewherein the hydrophobic groups and hydrophilic groups of thenon-saccharide segments are sized and distributed to mitigate againstprotein adhesion.

It is another object of the present disclosure to provide a substancethat mitigates protein adhesion and promotes cellular infiltration, inparticular the substance attracts cells responsible forneovascularization.

It is another object of the present disclosure to provide a substancethat can be implanted in living tissue to promote healing of a woundwhich does not promote a strong foreign body response, does not resultin a chronic inflammatory response, does not become thickly encapsulatedwith fibrotic, avascular tissue, and early in the healing processencourages vessel formation and infiltration of metabolic tissue.

It is another object of the present disclosure to provide an implantablecoating that shields from living tissue a material that incites a strongforeign body response.

It is another object of the present disclosure to provide an implantablecoating that temporarily shields from living tissue a material thatincites a strong foreign body response, such that metabolic tissue caninfiltrate the coated material prior to the coating being bioabsorbed.

It is another object of the present disclosure to provide a shieldingcoating to a structural soft tissue repair device, e.g., a surgicalmesh.

It is another object of the present disclosure to provide a surgicalbarrier, one side of which blocks tissue adhesions and the other side ofwhich promotes tissue adhesion and ingrowth.

It is another object of the present disclosure to provide abiocompatible material for forming absorbable fibers which can be woven,knitted, or otherwise constructed into mesh structure suitable forrepair of soft tissue defects.

It is another object of the present disclosure to provide an absorbablepolyurethane material which does not alter the local pH of the tissueenvironment in which the material resides.

It is another object of the present disclosure to provide an absorbablepolyurethane material which swells when exposed to aqueous solutions,and thus is suitable for the uptake of therapeutic agents dissolved inwater.

It is another object of the present disclosure to provide a superiorhyaluronic acid structure comprised of segments of hyaluronic acidjoined by urea or urethane links, said links modifying thehydrophilicity of the hyaluronic acid, and providing improved stabilityin a living tissue environment.

It is another object of the present disclosure to provide a superiorhyaluronic acid structure comprised of segments of hyaluronic acidjoined by urea or urethane links, said links modifying thehydrophilicity of the hyaluronic acid, and providing improved stabilityin a living tissue environment; and additionally said hyaluronic acidurea/urethane segment is joined to ether or ester segments, singly or incopolymer form. Said hyaluronic acid urea/urethane segments and saidether or ester segments randomly or periodically joined. Furthermore,the size and distribution of said hyaluronic acid urea/urethane segmentsand said ether or ester segments are chosen so as to mitigate proteinadhesion.

It is another object of the present disclosure to introduce the notionof a generalized Vroman effect, which is responsible for identificationof foreign objects in the body, and involves a series of proteinadsorption and desorption on a foreign body, which when blocked orreduced renders an implant bio-transparent to the foreign body response.And it is an object of the present disclosure to provide a material thatmitigates foreign body response by rendering an implant bio-transparent.

It is another object of the present disclosure to provide an implantablematerial that is devoid of collagen, but promotes neovascularization ofa wound repair site and encourages the body to form its own collagenduring the healing process which complements the formation of metabolictissue.

It is another object of the present disclosure to provide a substituteto biologics, or any material derived from living tissue extracellularmatrix devoid of antigenic material, such that it does not elicit aforeign body response due to the present of allograph collagen or thepresence of crosslinks that alter the structure of living collagen andhyaluronic acid complexes.

It is another object of the present disclosure to provide a syntheticsubstitute to biologics which is suitable for used in failed orcontaminated tissue repair sites.

It is another object of the present disclosure to provide a mesh, eithercoated or comprised of the material of the present disclosure, for usein pelvic floor repair where tissue adhesions are prevalent.

It is another object of the present disclosure to provide a polymerwhich resists microbial adhesion by mitigating the generalized Vromaneffect.

Embodiments according to the current disclosure can be described asmethods of making disclosure compositions. For instance, some disclosuremethods comprise reacting prepolymers of the present disclosure on amesh comprised of fibers such that the prepolymers polymerizes on saidmesh fibers and thereby completely covers said fibers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates domains of hydrophilic and hydrophobic zones in anembodiment of the copolymer of the present disclosure.

FIG. 2 illustrates the charge induced bonding between adjacent hardsegment domains in polymer chains comprised of hyaluronic acidpolymerized with urethane or urea links.

FIG. 3 illustrates the repulsion of proteins from an embodiment of acopolymer of the present disclosure.

FIG. 4 illustrates the condition of chronic foreign body response in thesituation of a synthetic mesh used to structurally support a wound siteand the paucity of vessels in the region of healing.

FIG. 5 illustrates the condition of chronic foreign body response in thesituation of a biologic material used to structurally support a woundsite and the effect on vascularity as the wound site remodels resultingin a paucity of vessels in the region of healing.

FIG. 6 illustrates the condition of healing using the present disclosurewherein the wound site is structurally intact and vascularized.

FIG. 7 illustrates a surgical adhesion barrier comprised of ananti-adhesive side and a tissue reparative side.

FIG. 8 illustrates an absorbable surgical mesh comprised of the presentpolymer, and the anti-adhesive functionality, and the ingrowthfunctionality.

FIG. 9 illustrates a composite surgical mesh comprised of ananti-adhesion film coupled to a mesh coated with the polymer of thepresent disclosure.

DETAILED DESCRIPTION

Provided herein is a biocompatible composition comprising apolymerization product of an anionic polysaccharide, a diisocyanate, anda linker, wherein the linker comprises i) an ether group, an estergroup, or a combination thereof and, ii) a chain extender comprising ahydroxyl group, a thiol group, an amine group, or a combination thereof.In certain embodiments, the copolymers are capable of reducing orpreventing protein adsorption, and more particularly, the Vroman effectwhen implanted in living tissue.

In certain embodiments, the polymerization product comprises a copolymerof a prepolymer and the linker, wherein the prepolymer comprises acopolymer of the anionic polysaccharide and the diisocyanate. Forexample, the prepolymer, may comprise anionic polysaccharide blocks Aand urea or urethane blocks B, such that the prepolymer comprises atleast one segment represented by ABBA, representing two polysaccharideblocks A joined by a diisocyanate such that two urethane or urea blocksB are produced. In further embodiments, the prepolymer includes at leastone segment represented by I[BABBAB]_(n)I, independently for eachoccurrence, A represents a polysaccharide block, B represents a urethaneor urea block, I represents an isocyanate and n represents an integerranging from about 1 to about 10,000. Thus, the urethane or urea blocksB are derived from the reaction of the isocyanate groups of thediisocyanate with hydroxyl or amine groups on the anionicpolysaccharide. In some embodiments, the polysaccharide blocks A arebound to a plurality of urethane or urea blocks B. For example, anydesired number of free hydroxyl groups of the polysaccharide may becoupled to a diisocyanate, such that the polysaccharide blocks A arecovalently bound to multiple urea or urethane blocks B. Such structuresare further capable of providing cross-linked copolymers.

Thus, certain embodiments can be described as a composition comprisingthe polymerization product of a polymeric isocyanate said polymericportion comprising anionic polysaccharide blocks A, urethane blocks Band isocyanate groups I with structure IBABBABI reacted with hydroxyland amine chain extenders E containing an ether C, for example of theform ECE. Thus when reacted, IBABBABI and ECE form structures likeIBABBABBCBBABBABI. These structures are differentiated functionally frompolyol multi-isocyanates of the form IBCBI reacted with polysaccharidesA, where the minimum form is ABBCBBA, and there is no occurrence of thesequence ABBA.

In certain embodiments, the linker comprises at least one segmentrepresented by ECE, wherein, independently for each occurrence, Crepresents an ether block, an ester block or a combination thereof, andE represents a chain extender comprising a hydroxyl, thiol, or an aminegroup. Thus, upon reaction of a prepolymer represented byI[BABBAB]_(n)I, as described above, with a linker represented by ECE,the resulting polymerization product comprises at least one segmentrepresented by [BABBAB]_(n)BCB[BABBAB]_(n), wherein, independently foreach occurrence, A represents a polysaccharide block, B represents aurea or urethane block, C represents an ether block, and ester block ora combination thereof, and n represents an integer ranging from 1 to10,000. In certain embodiments, the [BABBAB] blocks are hydrophilic andabsorbable relative to the [BCB] blocks. In alternative embodiments, apolymerization product comprises at least one segment represented by[BABBAB]_(n)[BC_(m)B]_(p), wherein the [BABBAB] segments and [BC_(m)B]segments are randomly associated. In theses blocks, numerals m, n, p areintegers from 1-10,000. The moieties consist of anionic polysaccharideblocks A, urethane blocks B and isocyanate groups I with structureIBABBABI reacted with hydroxyl J and amine K chain extenders Econtaining an ether or ester C, for example E is of the form JCJ or KEK.The C-moiety is preferably comprised of ether groups. Thus when reacted,IBABBABI and ECE form structures like IBABBABBCBBABBABI. Thesestructures are novel in the occurrence of the sequence ABBA.Consequently, the compositions of the present invention have at leastone segment as represented by the following formulas: ABBA, representingtwo polysaccharides A joined by a diisocyanate converted into twourethane links.

Accordingly, in certain embodiments when the copolymer of the prepolymerand the linker comprises at least one segment represented by[BABBAB]_(n)BCB[BABBAB]_(n), the copolymer may comprise a linearstructure, a cross-linked structure, or a mixture thereof. In certainembodiments, the copolymer is in a prepolymeric form, for example,further comprising one or more isocyanate groups. A non-limiting exampleof such a copolymer comprises at least one segment represented byI[BABBAB]_(n)BCB[BABBAB]_(n)I. Such prepolymeric forms may be furtherpolymerized via urea or urethane linkages. In other embodiments, theisocyanate groups of the prepolymeric form may be end-capped by thereaction of the isocyanate group with water, an alcohol or an amine.

It is to be understood that the aforementioned polymeric segmentencompasses structures in which the polysaccharide blocks A arecovalently bound to a plurality of urea or urethane blocks B. Forexample, any desired number of free hydroxyl groups of thepolysaccharide may be coupled to a desired number of diisocyanates, suchthat the polysaccharide blocks A are covalently bound to multiplepolyurethane blocks B. The polyurethane blocks B optionally comprise anisocyanate. In embodiments wherein urethane linkages between the C blockand the A block are desired, then the chain extender comprises ahydroxyl or thiol group. In embodiments wherein urea linkages aredesired, the chain extender comprises an amino group.

In alternative embodiments, the polymerization product comprises acopolymer of a prepolymer and the anionic polysaccharide, wherein theprepolymer comprises a copolymer of the linker and the diisocyanate. Inthese embodiments, the prepolymer is derived from the reaction of thelinker with the diisocyanate to produce a copolymer having at least onesegment represented by IBCBI. Thus, the polymerization product of alinker represented by ECE and a prepolymer represented by IBCBIcomprises at least one segment represented by ABBCBBA, whereinindependently for each occurrence, A represents a polysaccharide block,B represents a urea or urethane block, and C represents an ether block,an ester block, or a combination thereof.

It is to be understood that the aforementioned polymeric segment ABBCBBAencompasses structures in which the polysaccharide blocks A arecovalently bound to a plurality of urethane or urea blocks B. Forexample, any desired number of free hydroxyl groups of thepolysaccharide may be coupled to a desired number of linkers of the formECE, such that the polysaccharide blocks A are covalently bound tomultiple C blocks via a urea or urethane. The polymerization productoptionally comprises an isocyanate. In these embodiments, the copolymermay be further polymerized to produce cross-linked structures.Alternatively, the may be end-capped by the reaction of the isocyanategroup with water, an alcohol or an amine.

In embodiments wherein urethane linkages between the C block and the Ablock are desired, then the chain extender comprises a hydroxyl or thiolgroup. In embodiments wherein urea linkages are desired, the chainextender comprises an amino group.

Examples of anionic polysaccharides useful in the present copolymersinclude, without limitation hyaluronic acid, glycosaminoglycans,aligantes, cellulose, carboxymethylcellulose, carboxymethylamylose,chondroitin-6-sulfate, dermatin sulfate, salts thereof and mixturesthereof. Accordingly, in some embodiments, the polysaccharide block A isderived from hyaluronic acid, glycosaminoglycans, aligantes, cellulose,carboxymethylcellulose, carboxymethylamylose, chondroitin-6-sulfate,dermatin sulfate, salts thereof and mixtures thereof. In certainembodiments, the anionic polysaccharide is hydrolytically labile, suchas a hyaluronic acid or a salt thereof. As used herein the term“hyaluronic acid” refers to hyaluronic acid and any of its hyaluronatesalts, including, for example, sodium hyaluronate, potassiumhyaluronate, magnesium hyaluronate, and calcium hyaluronate.

Hyaluronic acid comprises repeating units of D-glucoronic acid andD-N-acetylglucosamine, both of which contain hydroxyl groups. Hyaluronicacid is a naturally occurring mucopolysaccharide found, for example, insynovial fluid, in vitreous humor, in blood vessel walls and umbilicalcord, and in other connective tissues. The polysaccharide consists ofalternating N-acetyl-D-glucosamine and D-glucuronic acid residues joinedby alternating β 1-3 glucuronidic and β 1-4 glucosaminidic bonds. Inwater, hyaluronic acid dissolves to form a highly viscous fluid. Themolecular weight of hyaluronic acid isolated from natural sourcesgenerally falls within the range of 5×10⁴ up to 1×10⁷ daltons.

Hyaluronic acid is an example of a glycosaminoglycan. Some of the usefulproperties of glycosaminoglycans are: a) they are negatively chargedmolecules, b) they possess an extended conformation that imparts highviscosity when in solution, c) they are located primarily on the surfaceof cells or in the extracellular matrix, d) they have lowcompressibility in solution and, as a result, are ideal as aphysiological lubricating fluid, and e) their rigidity providesstructural integrity to cells and provides passageways between cells,allowing for cell migration. The glycosaminoglycans of highestphysiological importance are hyaluronan, chondroitin sulfate, heparin,heparan sulfate, dermatan sulfate, and keratan sulfate. Mostglycosaminoglycans bind covalently to a proteoglycan core proteinthrough specific oligosaccharide structures. Therefore, they are idealstructures for promoting healthy interface with extracellular matrix,and their combination with a polyurethane reduces the destructivecellular responses to foreign bodies.

Hyaluronic acid is readily soluble in water, but only sparingly solublein organic solvents. Unfortunately, isocyanates are readily converted toamines in the presence of water. Thus, in order to react hyaluronic acidwith an isocyanate in a manufacturing process, the hyaluronic acid canbe made soluble in a non-aqueous solvent. For example, hyaluronic acidmay be modified so that it is soluble in organic solvents to makepractical most manufacturing processes. One of the modification methodsis to modify hyaluronic acid with PEG and/or adding positive chargetridodecyl methyl ammonium chloride (TDMAC) to neutralize the negativecharges of hyaluronic acid to make the hyaluronic acid soluble in anorganic solvent. In certain embodiments, hyaluronic acid is modifiedwith ammonia to render it soluble in organic solvent.

Isocyanates react with hydroxyl groups of the anionic polysaccharides toform urethane links. Thus, an anionic polysaccharide can be converted toa polyisocyanate upon the reaction with a diisocyanate. In someembodiments, all or most of the hydroxyl groups of the polysaccharideare reacted with the diisocyanate. For example, at least 75% of thehydroxyl group may be reacted with diisocyanate. In other embodiments,75% to 100% of the hydroxyl groups are reacted with the diisocyanate,for example about 80%, 85%, 90%, 95%, 98 or 99% of the hydroxyl groupsare reacted with the diisocyanate. Prepolymers of a polysaccharide, suchas hyaluronic acid, and diisocyanate wherein most or all hydroxyl groupis capped with diisocyanate are more stable in storage. By way ofexample, upon reaction of a diisocyanate with a hyaluronic acid, thehyaluronic acid is converted to a polyisocyanate. Hyaluronicpolyisocyanates of the present disclosure may, in some embodiments, becomprised of multiply cross-linked hyaluronic acid blocks. Theseprepolymers may comprise some unreacted hydroxyl groups. In otherembodiments, all or most of the hydroxyl groups are reacted with thediisocyanate. Similar structures comprising urea links instead ofurethane links may be formed when the polysaccharide comprises aminegroups.

In certain embodiments, the diisocyanates are aliphatic, cycloaliphaticor aromatic. Additionally, the diisocyanate may be selected such thatits hydrolysis product is a biocompatible diamine. While not being boundby any particular theory, degradation by amine formation is contemplatedto be hindered relative to hydrolytic degradation of the polysaccharide,thereby suppressing amine formation. Examples of diisocyanates usefulfor producing the B blocks of the copolymers of the present disclosureinclude without limitation 1,4-thisocyanatobutane,1,2-diisocyanatoethane, lysine ester diisocyanate,1,5-diisocyanatopentane, toluene diisocyanate, isophorone diisocyanate,or any combination of these.

In an embodiment, the prepolymer of the anionic polysaccharide (such ashyaluronic acid) and the diisocyanate is hydrophilic, and itshydrophilicity can be adjusted by the choice of diisocyanate. While notbeing bound by any particular theory, it is believed that the role ofthe urethane linkage in the prepolymers of the present disclosure is tostabilize the anionic polysaccharide segment (e.g. hyaluronic acid)against degradation in vivo.

The linker can be employed to further adjust the overall hydrophilicityof the reaction product, in some embodiments. Linkers are moleculescomprising two or more chain extenders comprising functional groups,which are linked by a relatively stable chain. In certain embodiments,the functional groups are hydroxyls, thiols, amines, or combinationsthereof. The unreactive portion of the chain extender may comprise ethergroups, ester groups, or combinations thereof. In some embodiments, thechain comprises ether groups, such as ethylene oxides and propyleneoxides.

Thus, in certain embodiments, the linker comprises at least one segmentrepresented by ECE, wherein C represents an ether block, and ester blockor a mixture thereof, and E represents a chain extender comprising ahydroxyl or an amine group. C may be ethylene oxide and/or propyleneoxide copolymers. Additionally, C may be comprised of a hydroxyacid, ahydroxyacid composition, a hydroxyacid oligomer, an amino acid, an aminoacid composition, or an amino acid oligomer.

In certain embodiments, C comprises ether blocks, such as a polyalkyleneoxide. In particular embodiments, C represents a polyethylene oxide andpolypropylene oxide (PEO/PPO) chain. Examples of PEO/PPO includecommercially available PEO/PPO surfactants such as a Pluronics. In otherembodiments, C is derived from polyols such as Multranol, or otherpolyethers, such as Tetrathane. In other embodiments, C comprises ahydroxyacid, such as a hydroxyacid oligomer or polymer.

Ethylene oxides are relatively hydrophilic and propylene oxides arerelatively hydrophobic. The randomness and blockiness of ethyleneoxide/propylene oxide copolymers can be used to achieve the overallVroman modulation of the polymerized product. For example, thehydrophobicity can be employed to push water toward the hyaluronic acidblock, making degradation of the hyaluronic acid segments more likelycompared to degradation of the urethane links. In certain embodiments,the C block comprises ethylene oxide and propylene oxide monomers in anumber ratio ranging from about 65:35 to about 85:15 ethyleneoxide:propylene oxide. In other embodiments, the C block comprisesethylene oxide and propylene oxide monomers in a number ratio rangingfrom about 35:65 to about 15:85 ethylene oxide:propylene oxide. Thestability and hydrophilicity of polyethers can, in certain embodiments,be modulated by the relative concentrations of propylene oxide andethylene oxide blocks.

The C block also may comprise an ester, or an ester copolymerized withthe above-discussed ethers, for example an ether-ester copolymer. Theinclusion of an ester, in some embodiments, provides a degradable blockwithin the C block. In certain embodiments, the ester comprises ahydroxy acid, such as 2-hydroxyacids, including lactic acid or glycolicacid, 3-hydroxy acids such as 3-hydroxybutyric acid, 3-hydroxyvalericacid, 3-hydroxypropanoic acid, or 3-hydroxyhexanoic acid, 4-hydroxyacids, such as 4-hydroxybutyric acid, 4-hydroxy valeric acid,4-hydroxyhexanoic acid; or ε-hydroxy-caproic acid.

Other esters that provide a degradable C block include polycaprolactone,poly(D,L-lactide), poly(L-lactide), poly(D,L-lactide-co-L-lactide),poly(glycolide), poly(D,L-lactide-co-glycolide), poly(dioxanone),poly(4-hydroxybutyrate), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(hydroxybutyrate-co-hydroxyvalerate), poly(tyrosinederive carbonates), poly(tyrosine arylates), poly(imino carbonates),poly(trimethylene carbonate), poly(anhydrides), poly(orthoesters),poly(ester amides) or their mixtures.

In certain embodiments, the C block further includes a urea or urethanelinkage, and more particularly, a urethane linkage. For example, the Cblock can be derived from the product of a polyether and adiisoacyanate, or a polyether, a polyester and a diisocyanate.

Some polyurethanes are both biostable and hydrophilic. Polyurethanes arenot usually considered bioabsorbable polymers because they contain ahydrolytically stable urethane linkage. The stability can also bemodulated by the addition of polysaccharides, which is a preferreddegradation pathway over degradation of urethane blocks into amines. Thestability of polyurethanes can be enhanced by crosslinking, the use ofaromatic rather than aliphatic isocyanates, and the inclusion ofdegradable hydrophilic blocks. These degradable blocks can be made morebiostable by juxtaposition of urethane links, modifying a hydrolyticallyunstable compound into one capable of persisting in living tissue forseveral months. Incorporating hydrolytically labile groups into thepolymer backbone alters polyurethane biodegradability. Thus, in certainembodiments, compositions of varying stability in vivo can be produced.

In certain embodiments, the choice of urethane vs urea links between theprepolymers and the linker affect hydrophobicity of the polymerizedproduct. Hydrophilic segments are created, for example, whenpolyoxyalkylene chains and hyaluronic acid chains are predominantlyinterconnected by urea links. In this embodiment, at least 50 percent ofthe individual oxyalkylene groups may be oxyethylene groups. Hydrophobicsegments are created when polyoxyalkylene chains and hyaluronic acidchains are predominately interconnected by urethane links. In thisembodiment, substantially all of the oxyalkene groups can be ethyleneoxide.

In the production of urea links, diamines can be employed as chainextenders. Thus, in a linker comprising the segment ECE, E represents achain extender comprising an amino group. These amines can be used toend-cap polyoxyalkylene chains or they may be used unaltered. Polyol Cblocks can be amidated by reacting a polyol with di-, tri- or polyaminocompounds. An example of a diamino compound useful in this embodiment isNH₂CH₂CH₂(OCH₂CH₂)_(n)NH₂, where n=2 to 12. Other diamino or polyaminocompounds include; aliphatic di/tri/polyamines, such as; H₂N(CH₂)_(n)NH₂wherein n=0 to 6, hydroxy-di/tri/polyamines, such asH₂N(CH₂)_(n)(CHOH)_(m)NH₂, wherein n=0 to 2 and m=0 to 2. Examplesinclude 1,3-diamino-2-hydroxypropane, 1,3-diaminoacetone,2,5-diaminobenzenesulfonic acid, 3,5-diaminobenzoic acid,2,6-diaminopyridine, 2,5-diaminopyridine, 2,6-diaminopurine,1,4-butanediamine, 1,2-ethanediamine, 1,5-pentanediamine; lysine ester,arginine ester and mixtures thereof.

In some embodiments, the chain extender comprises an alcohol-amine, adiamine, a diol, a dithiol, or any combination of these. The diamine canbe selected from 1,4-butanediamine, lysine ester, 1,2-ethanediamine,arginine ethyl ester, 1,5-pentanediamine, or any combination of these.The diol can be selected from 1,3-propanediol, 1,2-propanediol,1,4-butanediol, 1,6-hexanediol, 1,10-decanediol, cyclohexanedimethanol,and poly(caprolactone)diol, 1,5-pentanediol, 1,4-cyclohexanediol,1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,12-dodecanediol,poly(caprolactone) diol, or any combination of these. Chain extendersuseful in the production of urethane links include 1,3-propanediol,1,2-propanediol, 1,4-butanediol, 1,6-hexanediol, 1,10-decanediol,cyclohexanedimethanol, and poly(caprolactone)diol, 1,5-pentanediol,1,4-cyclohexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol,1,12-dodecanediol, and caprolactone diol. Some embodiments specificallyexclude anyone or any combination of these diols. The diols can be usedto endcap the C blocks, for example, polyether blocks.

The isocyanate endcapping of the hydroxyl groups on the anionicpolysaccharides of the present disclosure can be performed usingsolvents. Useful solvents are dimethylsulfoxide, dimethylacetamide,dimethylformamide, tetrahydrofuran, 1,4-dioxane, and methylene chloride.Anhydrous conditions are required as water consumes isocyanate groups.The isocyanate endcapping can also be catalyzed with tin salts such astin (II) 2-ethylhexanoate and dibutyltin dilaurate.

In certain embodiments, the copolymers of the present disclosure arebiodegradable. “Biodegradable” in the present disclosure means that asubstance is not hydrolytically, oxidatively, or enzymatically stable,and is substantially broken down in an in vivo environment over a periodof about 1 to about 60 months, or about 6 to about 24 months, or about 6to about 12 months. For example, a biodegradable polymer is nothydrolytically, oxidatively, or enzymatically stable, and issubstantially broken down by the in vivo in any of the aforementionedtime periods. As used herein, “substantially broken down” means themechanical or biologic functionality of the biodegradable substance isreduced by at least half. This can be confirmed by use of appropriate invivo animal models, which allow the implant to be removed and analyzedat serial time points. A way of testing biodegradability is to immersethe substance in a solution that mimics the in vivo environment andmonitor its mean molecular weight loss over time. If the material haslost more than 50% of its mean molecular weight over a 6-month period,then it can be characterized as biodegradable.

Depending upon the reaction sequence and/or relative reactivity of themonomers, invention polymers or compositions can be more random-like ormore block-like. A polymeric composition C1 is more random-like than apolymeric composition C2 if the amount of information required todescribe C1 is greater than the amount of information required todescribe C2. For example, a polymeric composition comprised one type ofrepeating segments is less random than a polymeric composition comprisedof two types of repeating segments, and a maximally random polymericcomposition contains no repeating segments. A polymeric composition C1is more block-like than a polymeric composition C2 if the mean size ofsegments comprised of the same moiety or monomers of C2 is greater thanthe mean size of segments comprised of the same moiety of C2.

If the particular discussion of a polymer is silent regarding polymertopology, that discussion encompasses embodiments with a polymertopology selected from all topologies, random-like topologies,block-like topologies, random topologies, block topologies, andtopologies intermediate between random-like and block-like topologies.Moreover, in some embodiments the polymer is selected to excludepolymers with topologies selected from random-like, block-like, random,block, topologies intermediate between random-like and block-like, orany combination of these topologies.

For purposes of this disclosure, “Vroman modulation” means adjusting apolymer's randomness, blockiness, hydrophilicity, charge distribution,fractal dimension with respect to the distribution ofhydrophilic/hydrophobic units, etc., in order to substantially decreaseprotein adsorption, the number of adherent macrophages and inflammatorycells, the degree of inflammatory cell activation, and the concentrationof reactive oxygen species surrounding the implant. Preventing thegeneralized Vroman effect involves the formation of protein blockinghydrophilic domains around structural hydrophobic domains. In certainembodiments, the copolymers described herein comprise hydrophilicdomains and hydrophobic domains, as depicted in FIG. 1. Moreparticularly, the copolymers comprise protein-blocking hydrophilicdomains and structural hydrophobic domains. FIG. 1 illustrates domainsof hydrophilic 102 and hydrophobic 104 zones in a copolymer 100 of thepresent disclosure. There are two large-scale regions, the hydrophilicregion 102 occupied by a polysaccharide 106 and the hydrophobic regionoccupied by an ether, ester, or copolymer of ether and ester 108. Withinthese large-scale regions are small-scale regions. In one instance, thesmall-scale regions are hydrophobic segments 110 comprised of urea orurethane bonds. In another instance, the small-scale regions arehydrophobic segments comprised of esters or ethers. Within thesmall-scale regions are micro-scale regions. In one instance, within theurea or urethane small-regions 110 is either an aliphatic group 112 oraromatic ring 114. The aliphatic micro-regions 112 are hydrophilicrelative to the aromatic micro-regions 114, but compared to thehydrophilic small-scale regions, both are hydrophobic. Within thesmall-scale ether regions there are micro-scale hydrophilic regions 116and hydrophobic regions 118. Examples of micro-scale hydrophilic regionsare ethylene oxides or glycols. Examples are micro-scale hydrophobicregions are propylene oxides or glycols. The small-scale ester regionsare generally more hydrophobic than the micro-scale ether regions. Amongthe ester moieties, there are variations in hydrophilicity that can beemployed in the present multi-scale architecture.

For example, hyaluronic acid and polyethylene glycol are both highlyhydrophilic, while on the other hand polypropylene and polyurethanes arehydrophobic. By combining these constituents, a biocompatiblecomposition can be synthesized, which prevents protein attachment andpossess volumetric stability and durability in the living tissueenvironment.

The structural stability of the polymers of the present disclosure in animplant environment are, in some embodiments, governed by crosslinks,which are easily formed in the instance of many polysaccharides becausethey comprise multiple hydroxyl groups. Thus, in certain embodiments,the copolymer is cross-linked. In certain embodiments, “cross-linked”means that a solid polymer is insoluble in solvents and thermallychanges chemical composition (degrades) prior to entering a liquidstate. Inn other embodiments, the copolymer is linear, or substantiallylinear. In general, the stability is enhanced by a greater proportion ofhydrophobic groups, but these have the disadvantage of attractingprotein adhesion, and consequently must be shielded by hydrophilicgroups since mitigation of the generalized Vroman effect is desired inpolymers of the present disclosure.

In other embodiments, greater structural durability can be achieved bythe use of small-scale hydrophobic regions interspersed in thelarge-scale hydrophilic polysaccharide regions. While thepolysaccharides tend to fill the regions between them with watermolecules, the hydrophobic regions tend to associate by chargeinteractions. This is a preferred approach to achieving cohesiveness ofa biopolymer compared to crosslinking, since such charge induced bondsare not structural.

FIG. 2 illustrates the polymeric configuration due to charge inducedbonding 200. The charge induced bonds 202 are induced between adjacenthard segment domains 204 in polymer chains 206 comprised of hyaluronicacid 208 polymerized with hard segment urethane or urea links. Asillustrated, hydrophilic channels 210 comprised of hyaluronic acid areformed by aligning hydrophilic hyaluronic acid segments 208.

Mitigation of the generalize Vroman effect involves blocking adhesion ofprotein to the polymer. FIG. 3 illustrates the repulsion of proteinsfrom the polymer of the present invention 300. The polymer is comprisedof large- 302, small- 304 and micro-scale 306 regions of hydrophilicityand large- 308, small- 310 and micro-scale 312 regions ofhydrophobicity. The relative hydrophilicity is always compared to localdomains of similar size, so in some cases a micro-scale hydrophilicregion may be more hydrophobic than a distant micro-scale hydrophobicregion. This is important since many proteins are small enough to beinfluenced by these micro-scale domains. Additionally, the overalldegradation mechanism of the polymer, whether the implant degrades asvisible flakes or molecular sized fragments depends on this multi-scalehierarchy. Once the shielding structure of hydrophilic segmentsjuxtaposed with hydrophobic segments is disassembled, then mitigation ofthe generalized Vroman effect fails. So it is important to maintain thisself-similar structure on many size scales, both to promote uniform andmolecular level degradation as well as preserve the generalized Vromanmitigation even if a fragment should is associated due to stress in theimplant environment. Consequently, the hydrophilic regions 302, 304, 306are always juxtaposed to hydrophobic regions 308, 310, 312. However, itshould be understood that the present invention intends to construct netlarge-scale hydrophobic regions and net large-scale hydrophilic regions,but their interaction with proteins, which are orders of magnitudesmaller than cells, is intended to be mitigated by the small-scalebalancing of hydrophobic and hydrophilic domains. A similar architectureresides at the micro-scale level relative to the small-scale level.Multi-scale hydrophobic/hydrophilic balancing at every level combinedwith distinct domain formation at the large-scale (cellular) level,preserves the protein blocking functionality while promoting the cellinfiltrations functionality. And in particular, presents an architecturethat promotes endothelial cell infiltration, the formation of newvessels, and the support of metabolic tissue.

Returning to FIG. 3, hydrophilic regions large-scale 302, small-scale304, micro-scale 306 associate with water and create a water envelope314, 316, 318, respectively. Water envelopes 314, 316, 318 shield thestructural hydrophobic regions large-scale 308, small-scale 310, andmicro-scale 312. When a microbe 330 (small- to micro-scale) or protein332 (small- to micro-scale) attempts to attach to the polymer of thepresent invention 300 it may attach as in 320 or be repelled bystochastic processes as in 322. In the case where attachment occurs 320,water within the hydrophilic domain 324 is in exchange with the tissueenvironment and leaves the polymer surface 326 disrupting attachedspecies 320 and sending it exterior to the polymer 328. The in-flux andout-flux of water, derived from the tissue, is responsible for thewashing effect of the present polymer, and shields it from protein ormicrobial adhesion.

The present disclosure also provides medical devices comprising thecompositions described herein. The devices are capable of preventing orreducing protein adsorption when placed in vivo, particularly the Vromaneffect. More specifically, the devices comprise a composition that canprevent or at least reduce the build-up of a denatured layer of proteinon its surface or on the device coating. In embodiment wherein thecomposition comprises hyaluronic acid, the hyaluronic acid blocks arereleased as the copolymer degrades in vivo, thereby directing cellularinfiltration and neovascularization in the absence of the formation ofinhibiting fibrosis, and additionally directing beneficial healing withmetabolic tissue without the need for releasing pharmaceutically ortherapeutically active agents. The compositions described herein can becast into films or extruded into fibers, which can further be woven orknitted in to fabrics and used to form an implantable mesh. The devicesand coatings can be prepared by allowing a prepolymeric form, whichcomprises isocyanate groups, to polymerize in the presence of water toform urea links. In other embodiments, the prepolymeric form can bepolymerized under anhydrous conditions to form urethane links. In someembodiments, the devices described herein are absorbable in vivo, but donot substantially alter the local pH of the tissue environment in whichthe device is implanted.

In certain embodiments, the device is a mesh or a tissue scaffoldcomprising the aforementioned composition. In some embodiments, the meshcomprises a coating of the composition comprising any of theaforementioned polymerization products. For example, the mesh can be apolypropylene mesh comprising a coating of a composition of the presentdisclosure. In other embodiments, the mesh comprises fibers comprisingthe aforementioned composition. Such fibers can be prepared, forexample, by extruding a composition described above. In certainembodiments, the mesh is a composite mesh, further comprising ananti-adhesive film. The meshes described herein are useful in softtissue repair, wherein tissue adhesions are prevalent, such as pelvicfloor surgeries.

In another embodiment, the device is a film comprising the compositiondescribed here. A film is prepared, in come embodiments, by allowing aprepolymeric form, which comprises isocyanate groups, to polymerize inthe presence of water to form urea links. In other embodiments, theprepolymeric form can be polymerized under anhydrous conditions to formurethane links. In other embodiments, the device is a composite filmcomprising the film of the composition described herein coupled to ananti-adhesive film.

In certain embodiments, a composite device or coating may be formed ofmultiple layers. For example, a first layer may comprise a compositiondescribed herein, wherein the C block comprises all or mostly etherblocks, and a second layer may comprise a composition described hereinwherein the C block comprises all or mostly ester blocks. In anembodiment, the device or coating comprises an inner layer comprisingether blocks and an outer layer comprising ester blocks. In theseembodiments, the outer layer is absorbable while the inner layer isnon-absorbable. In another embodiment, the inner layer comprisesabsorbable ester blocks and the outer layer comprises non-absorbableether blocks. Thus, the inner layer is absorbable while the outer layeris non-absorbable.

In these or other embodiments, the medical device further comprises atherapeutic agent. The following types of therapeutic agents are foundin some embodiments: proteins, peptides, antiproliferatives,antineoplastics, antiinflammatories, antiplatelets, anticoagulants,antifibrins, antithrombins, antimitotics, antibiotics, antioxidants, ortheir mixtures.

In certain embodiments, the implantable medical device is formedproviding by number, molecular weight, and combinations of these, ratiosof hydrophilic and hydrophobic domains that are self-similar on multiplesize scales. In a further embodiment, an implantable medical device isformed by providing by number, molecular weight, and combinations ofthese, ratios of hydrophilic and hydrophobic domains that areself-similar on multiple size scales and possessing a fractal dimensionof between 1.3 and 1.8.

The present disclosure further provides methods of reducing orpreventing protein adhesions in vivo, and more particularly the Vromaneffect, comprising providing a composition as described herein. Thecompositions may be administered to a subject in the form of the medicaldevices described above. In the present methods, the foreign bodyresponse to an implant is reduced or prevented. The present disclosurefurther provides a method of using combinations of hydrophobic andhydrophilic domains within an implantable copolymer to lessen thequantity of protein adhesion to the implant, such that the foreign bodyresponse of the tissue to said copolymer is reduced. In certainembodiments, the present methods increase the in situ durability of anabsorbable polymer implant by placing hard segment urea or urethanelinks between absorbable segments in said polymer.

Capsule formation and remodeling of soft tissue repair prosthetics isresponsible for reduced vascularization of a wound site. Vascularizationof a wound site progresses by two mechanisms: sprouting andintussusception, the later occurring in resource starved environments.Sprouting angiogenesis begins with biological signals known asangiogenic growth factors that activate receptors present on endothelialcells present in pre-existing blood vessels. The activated endothelialcells begin to release enzymes called proteases that degrade thebasement membrane to allow endothelial cells to escape from the original(parent) vessel walls. The endothelial cells then proliferate into thesurrounding matrix and form solid sprouts connecting neighboringvessels. As sprouts extend toward the source of the angiogenic stimulus,endothelial cells migrate in tandem, using adhesion molecules, theequivalent of cellular grappling hooks, called integrins. These sproutsthen form loops to become a full-fledged vessel lumen as cells migrateto the site of angiogenesis. Sprouting occurs at a rate of severalmillimeters per day, and enables new vessels to grow across gaps in thevasculature. Intussusception involves a capillary wall extending intothe lumen to split a single vessel in two. The two opposing capillarywalls establish a zone of contact. The endothelial cell junctions arereorganized and the vessel bilayer is perforated to allow growth factorsand cells to penetrate into the lumen. A core is formed between the twonew vessels at the zone of contact that is filled with pericytes andmyofibroblasts. These cells begin laying collagen fibers into the coreto provide an extracellular matrix for growth of the vessel lumen.Finally, the core is fleshed out with no alterations to the basicstructure. Intussusception is important because it is a reorganizationof existing cells. It allows a vast increase in the number ofcapillaries without a corresponding increase in the number ofendothelial cells.

The deposition of collagen in association with the formation of newvessels is critical to vascularization of a wound site, and thisstructured collagen formation is performed in conjunction with cellularscaffolding. Thus the development of dense, disordered collagen(connective tissue) at a wound site serves an acute purpose of sealing,bridging and structurally buttressing a tissue defect. However thisacute response blocks vascularization of the region. Furthermore, thistype of collagen formation is sometimes called scarring, which is aconfluent form of connective tissue characterized by contraction, lossof volume and mass. Therefore any neovascular that may form into thefibrous mass, and typically it does not, would be sheared off in thecontracting mass, resulting in loss of blood flow and atrophy of theneovessels.

FIG. 4 illustrates the condition of chronic foreign body response in thesituation of a synthetic mesh used to structurally support a wound siteand the paucity of vessels in the region of healing 400. Shown in crosssection, a mesh 402 bridges a tissue defect 404 connecting wound edges406. The material of the mesh 402 activates a strong foreign bodyresponse which results in the tissue defect 404 filling with dense,disorganized collagen 408. Sprouting vessels 410 are hindered in theireffort to penetrate the living tissue/scar interface 412.Coincidentally, dense, disorganized collagen encapsulates 414 the mesh402. Encapsulation 414 similarly blocks vessel infiltration.Furthermore, if the mesh 402 is particularly hydrophobic the thickness416 of encapsulation 414 increases with time, further preventingneovascularization of mesh 402. Chronically, vascularization of the mesh402 and tissue defect 404 is hindered by confluence or contraction ofthe established disordered collagen.

FIG. 5 illustrates the condition of chronic foreign body response in thesituation of a biologic material used to structurally support a woundsite and the effect on vascularity as the wound site remodels resultingin a paucity of vessels in the region of healing 500. Shown in crosssection, a biologic 502 bridges a tissue defect 504 connecting woundedges 506. One of the anticipated benefits of biologics 502 is that theyretain the extracellular matrix of the biological structure from whichthey were harvested. While these structures do promote angiogenesis 508into the biologic material 502, pre-existing collagen 510 in theextracellular matrix 512 or artificial crosslinks 514 formed betweencollagen 510 and hyaluronic acid 516 comprising extracellular matrix 512in the biologic 502 provides for protein attachment 518, which thensignals a foreign body response resulting in deposition of disorderedcollagen 520 which blocks or reduces the density of neovascularization522. The resulting inflammatory response contributes to degradation ofthe mesh and subsequent biologic contraction 524. The interface 526between biologic 502 and Wound edges 506 is disrupted by contraction 524shearing off or occluding 528 neovascularization 522.

FIG. 6 illustrates the condition of healing using the present disclosurewherein the wound site is structurally intact and vascularized 600.Shown in cross section, a coated mesh of the present disclosure 602bridges a tissue defect 604 connecting wound edges 606. The mesh iscomprised of polypropylene fiber 608 coated with hyaluronic acidpolyurethane 610. The coating 610 is comprised generally of hydrophobicstructural segments 612 and hydrophilic protein blocking segments 614.The mechanism for protein blocking is illustrated in FIG. 3. Thehyaluronic acid residing in the hydrophilic segments 614 promotesneovascularization 616. The absence of allograph collagen, and moregenerally protein attachment sites, is responsible for a reduced foreignbody response and the deposition of disorder collagen. Therefore, theneovascularization 616 results in ordered collagen deposition 618 whichserves to bridge the porous structure 620 and resulting in metabolictissue 622 incorporating coated mesh 602. Metabolic tissue 622 is stablesince it is not perceived as scar tissue, and thus is not remodeled.After metabolic tissue 622 incorporates coated mesh 602 the need forcoating 610 is removed, and beneficially resorbs into the body. Thestructural element 608 remains, which is beneficial in maintaining thestructural stability of the wound site, which can be subject toreherniation as disordered collagen 624 formed in tissue defect 604 isremodeled. This stability of the wound site promotes healthyrevascularization of tissue defect 604.

FIG. 7 illustrates a surgical adhesion barrier 700 comprised of ananti-adhesive side 702 and a tissue reparative side 704. Theanti-adhesion side may be any of known anti-adhesion devices, e.g.,polylactic acid, copolymers of hyaluronic acid and cellulose,polytetrafluoroethane, etc. The anti-adhesive side 702 preferably takeslonger to absorb than the reparative side 704 or is not absorbable.Depicted in cross section is the adhesion barrier 700 in contact with atissue defect 706 and defect edges 708. Anti-adhesive side 702 preventsthe establishment of connective tissue between adjacent tissue layer 710and defect edges 708. The reparative side 704 promotes ingrowth andvascularization 712 by providing a rapidly degrading component 714 and apersistent component 716 which form macroscopic hydrophobic 718 andhydrophilic 720 domains. The hydrophilic domains 720 resorb firstattracting cellular infiltration and providing porosity for ingrowth andvascularization. Prior to implant resorption and loss of structuralintegrity a network of living cells and vasculature 722 bridges defectedges 708. This architecture further supports revascularization oftissue defect 706.

FIG. 8 illustrates in cross section 800 an absorbable surgical mesh 802comprised of the present polymer, and the anti-adhesive functionality,and the ingrowth functionality. By not evoking a strong foreign bodyresponse the collagen deposition necessary for adhesion formation isless prevalent. While generally, mesh 802 will not block adhesions asreliably as a film construct, it will form fewer and weaker adhesionscompared to an uncoated permanent mesh. Adhesions that form maysubsequently be released as mesh 802 degrades. Shown is a tissue defect804, defect edges 806, and adjacent tissue layer 808. If adhesion 810attaches at mesh surface 812, mesh molecules 814 eventually resorbcausing adhesion 810 to detach from the mesh 816. The ingrowthfunctionality is similar to that described in FIG. 3 for a coated meshconstruct.

FIG. 9 illustrates in cross section 900 a composite surgical mesh 902comprised of an anti-adhesion film 904 coupled to a mesh 906 coated withthe polymer of the present disclosure. The coating may function to joinanti-adhesion film 904 to mesh 906. As coating 908 degrades asillustrated at location 910 a gap is formed through which vascularizedtissue 912 may grow. Preferably, mesh 906 is substantially ingrown withvascularized tissue 912 prior to loss of functionality of theanti-adhesion film 904.

Additional embodiments of the present disclosure are listed below. It isanother object of the present disclosure to provide a substance whereinthe hydrophobic groups and hydrophilic groups of the non-saccharidesegments are sized and distributed to mitigate against protein adhesion.

In certain embodiments, the compositions described herein mitigateprotein adhesion and promotes cellular infiltration, in particular thesubstance attracts cells responsible for neovascularization. In certainembodiments, the compositions described herein can be implanted inliving tissue to promote healing of a wound which does not promote astrong foreign body response, while preventing a chronic inflammatoryresponse. Furthermore, the compositions, in certain embodiments, do notbecome thickly encapsulated with fibrotic, avascular tissue, and earlyin the healing process encourages vessel formation and infiltration ofmetabolic tissue.

In other embodiments, the present disclosure provides an implantablecoating that shields from living tissue a material that incites a strongforeign body response. Additional embodiments, of the present disclosureprovide an implantable coating that temporarily shields from livingtissue a material that incites a strong foreign body response, such thatmetabolic tissue can infiltrate the coated material prior to the coatingbeing bioabsorbed.

Further embodiments provide a shielding coating to a structural softtissue repair device, e.g., a surgical mesh. Other embodiments provide asurgical barrier, one side of which blocks tissue adhesions and theother side of which promotes tissue adhesion and ingrowth. In anotherembodiment, a biocompatible material is provided for forming absorbablefibers which can be woven, knitted, or otherwise constructed into meshstructure suitable for repair of soft tissue defects.

In other embodiments, the compositions described herein comprise anabsorbable polyurethane material, which does not alter the local pH ofthe tissue environment in which the material resides. The polyurethanematerial, in certain embodiments, swells when exposed to aqueoussolutions, and thus is suitable for the uptake of therapeutic agentsdissolved in water.

In another embodiment, the composition described herein comprisessegments of hyaluronic acid joined by urea or urethane links, said linksmodifying the hydrophilicity of the hyaluronic acid, and providingimproved stability in a living tissue environment; and additionally saidhyaluronic acid urea/urethane segments are joined to ether or estersegments, singly or in copolymer form. The hyaluronic acid urea/urethanesegments and said ether or ester segments can be randomly orperiodically joined. Furthermore, the size and distribution of saidhyaluronic acid urea/urethane segments and said ether or ester segmentsare chosen so as to mitigate protein adhesion.

It is another object of the present disclosure to reduce or prevent theVroman effect. When the Vroman effect is blocked, an implant is renderedbiotransparent to the foreign body response. Thus, the compositionsherein, in certain embodiments, render medical devices, such as implantmaterials, biotransparent.

In other embodiments, the compositions described above are free fromcollagen. The compositions, in these embodiments, can promoteneovascularization of a wound repair site and encourages the formationof endogenous collagen during the healing process.

In other embodiments, the disclosure provides methods of making thepresent compositions and devices. For instance, the methods can comprisereacting prepolymers of the present disclosure on a mesh comprised offibers such that the prepolymers polymerizes on said mesh fibers andthereby coats said fibers.

All references to singular characteristics or limitations of the presentdisclosure shall include the corresponding plural characteristic orlimitation, and vice versa, unless otherwise specified or clearlyimplied to the contrary by the context in which the reference is made.

All combinations of method or process steps as used herein can beperformed in any order, unless otherwise specified or clearly implied tothe contrary by the context in which the referenced combination is made.

The methods and compositions of the present disclosure, includingcomponents thereof, can comprise, consist of, or consist essentially ofthe essential elements and limitations of the embodiments describedherein, as well as any additional or optional ingredients, components orlimitations described herein or otherwise useful in nutritionalcompositions.

As used herein, the term “about” should be construed to refer to both ofthe numbers specified in any range. Any reference to a range should beconsidered as providing support for any subset within that range.

EXAMPLES

Examples are provided to illustrate some embodiments of the compositionsand devices of the present disclosure but should not be interpreted asany limitation thereon. Other embodiments within the scope of the claimsherein will be apparent to one skilled in the art from the considerationof the specification or practice of the nutritional composition ormethods disclosed herein. It is intended that the specification,together with the example, be considered to be exemplary only, with thescope and spirit of the disclosure being indicated by the claims whichfollow the examples. The source of chemicals employed in these examplesis Sigma-Aldrich (Milwaukee, Wis.) unless otherwise noted.

Example 1: Polyethylene Oxide/Polypropylene Oxide Copolymers

Water soluble tri-block copolymers of polyethylene oxide (PEO) andpolypropylene oxide (PPO) are commercially available non-ionicmacromolecular surface active agents. Variation of the copolymercomposition (PPO/PEO ratio) and molecular weight (PEO and PPO blocklengths) during synthesis leads to the production of molecules withdiffering properties. Unfortunately, commercially available forms employblock structures that are typically larger than desired in certainembodiments of the present disclosure.

Since PEO is more reactive than PPO, fine scale block structures cannotbe formed by merely placing the ratio amounts of PEO and PPO together ina reactor. Alternating segments of PEO and PPO can be synthesized by thesequential addition of first propylene oxide (PO) and then ethyleneoxide (EO). These oxyalkylation steps are carried out in the presence ofan alkaline catalyst, for example, sodium or potassium hydroxide. Thecatalyst is then neutralized and removed from the final product. Byalternating additions of EO and PO one can make copolymers of particularPPO/PEO composition while varying the molecular weight of the PPOblocks. Thus a complete grid of copolymers are realizable, the gridcomprised of constant PPO/PEO composition on the vertical axis andconstant PPO block molecular weight on the horizontal axis.

Example 2: Hyaluronan Isocyanate

Hyaluronan is comprised of repeating segments of C₁₄H₂₁NO₁₁, eachcontaining 5 hydroxyl groups (OH). To form a diisocyanate of hyaluronanone reacts a quantity of diisocyanate containing 2 moles of NCO greaterthan the number of moles of OH. Thus, for a hyaluronan containing 1 unitof C₁₄H₂₁NO₁₁ per molecule, 1 mole of hyaluronan molecules is to bereacted with 7 moles of diisocyanate. The reaction is performed in anorganic solvent, where the hyaluronan is altered by ammonia to make itsoluble in an organic solvent, such as tetrahydrofuran. A small amountof tin catalyst is added to promote urethane link formation between thehydroxyls of the hyaluronan and the isocyanate groups of thediisocyanate. To discourage chain extension, the hyaluronan is firstdissolved in organic solvent and set aside. The reactor is charged withcatalyst and diisocyanate and heated to 80 degrees C. The hyaluronansolution is slowly added to the reactor and the exotherm monitored.Complete reaction is indicated when the exotherm subsides.Alternatively, one can measure the % NCO at each step to verify all thehydroxyl groups on the hyaluronan are endcapped with isocyanate.

When all the hyaluronan is added to the reactor the reaction is rununtil the desired % NCO is reached. % NCO is measured by conventionallyby dibutylamine titration. The reaction is complete when 2 moles of NCOare measured for every mole of product molecule. Ideally there is only 1C₁₄H₂₁NO₁₁ unit per product molecule. However, in other applications aspectrum of product molecules containing a range of C₁₄H₂₁NO₁₁ unit perproduct molecule is desired. The desired polydispersity can be obtainedby adjusting the amount of NCO used, and verifying with GPC and % NCOmeasurements. In any one reaction, the dispersity of molecular weightsof product molecules will be Gaussian around a desired mean. Multi-modaldistributions can be obtained by mixing the reaction product of multiplereactions. Hyaluronan isocyanates of higher isocyanate functionality canbe synthesized by adjusting the ratio of OH groups to isocyanate groupsin the reaction mix.

Example 3: Hyaluronan Polyurethane

A polyalkylene copolymer of PPO and PEO is synthesized according toEXAMPLE 1, wherein the PEO blocks contain 3 propylene oxide units, thePPO blocks contain 1 ethylene oxide unit, and these PEO and PPO blocksalternate, wherein the first block is a PEO and the last block is a PPO.The number of functional OH groups per molecule is approximately 2. Ahyaluronan diisocyanate is synthesized according to EXAMPLE 2 whereinthe molecular weight of the hyaluronan diisocyanate is approximately 3times the molecular weight of the polyalkylene copolymer.

If the polyalkylene component or the hyaluronan diisocyanate componentsare not in liquid form at a reaction temperature of approximately 80degrees C., then these components are dissolved in an organic solventdevoid of OH groups. The reactor is charged with 1 mole of hyaluronandiisocyanate and heated to 80 degrees C. The polalkylene copolymer isadded slowly, waiting for the exotherm to subside after each addition.

If a prepolymeric form is desired, e.g., a reaction product that willpolymerize on a mesh, then the component amounts are chosen to result in2 moles of NCO per product molecule. Chains of arbitrary length ofhyaluronan and polyalkylene can be synthesized by choosing the amount ofisocyanate such that 2 moles of NCO remain per desired molecular weightof product molecule. In some cases, a prepolymeric form with 3 or higherisocyanate functionality per product molecule is desired, so that whenpolymerized on a medical device, the coating is cross-linked.Cross-linking of the polymer provides a coating that is more resistantto solvents or heat. Not every molecule must have higher functionalityto obtain a polymerization product that is cross-linked.

If a linear polymer is desired, wherein the reaction product can bedissolved in solvent and solution cast, or melted and extruded, thensome of the hyaluronan diisocyanate may be endcapped with amono-functional alcohol such as ethanol. The molecular weight of thereaction product is selected by the ratio of diisocyanate tomono-isocyanate hyaluronan in the reaction mix. Alternatively, the chainextension can be terminated in reaction by adding ethanol to thereaction mix when the desired molecular weight is obtained. In thisinstance an excess of ethanol can be used, which is driven off byevaporation when all the NCO groups are consumed.

Dibutylamine titration can be used to determine when a reaction is done.In particular, in the polymer case, the reaction is complete when allNCO groups are consumed. In the prepolymeric case, the reaction iscomplete when the NCO number per product molecule reaches a desiredvalue. In the case of crosslinking prepolymers the NCO number is greaterthan 2 per product molecule. In the case of non-crosslinkingprepolymeric forms the NCO number equals 2 per product molecule.

The product molecules and polymerized forms are characterized bypossessing in number ratio approximately 3 segments of hyaluronan persegment of polyalkylene. The polyalkyelene segment comprises in numberratio approximately 3 segments of ethylene oxide per segment ofpropylene oxide. The hyaluronan segment is more hydrophilic than thepolyalkylene segment. The ethylene oxide segment is more hydrophilicthan the propylene oxide segment. The urethane links between hyaluronanunits having a molecular weight ratio of urethane to hyaluronanapproximately the same as the molecular weight ratio of urethane topolyalkylene segments. The urethane links are more hydrophobic than thehyaluronan units or polyalkylene segments, the density of which can betailored to form hard segment association between urethane links withinthe bulk volume of the polymer.

Example 4: Coated Polypropylene Mesh

An absorbable coating is formed on a conventional polypropylene mesh bydissolving a prepolymer of EXAMPLE 3 in an organic solvent. Preferablythe organic solvent is devoid of OH groups, for example, acetone. Themesh can be coated by any number of techniques known in the industry.The mesh may be dipped, sprayed, brushed or otherwise coated with theprepolymers. Subsequent to coating, the mesh coating is allowed topolymerized by reaction with water in the atmosphere, therebypolymerizing by urea formation. Alternative difunctional polyols can beadded to the prepolymer. In this case, the prepolymer will have a finiteshelf-life and the molecular weight of the prepolymers solution willchange as a function of time. When the mesh is coated, thepolymerization can be forced by the addition of a catalyst, which canlater be washed off. In this case, polymerization occurs by theformation of urethane links. If urethane links alone are desired, thepolymerization phase must be carried out in a water-free atmosphere.

Example 5: Absorbable Mesh

Fibers of the polymers of EXAMPLE 3 can be made by heating to melt thepolymer and extruding in fiber form. This fiber can be used to weave orknit mesh structures.

Example 6: Anti-Adhesion Film

A film can be made of the polymers and prepolymers of EXAMPLE 3. In thecase where the prepolymer is used, the prepolymer is poured on a glasssurface and allowed to polymerize with water in the atmosphere.Alternatively the prepolymer is mixed with a diamine and poured on aglass surface to form urea links. In yet another embodiment, theprepolymer is mixed with a diol and catalyst to form urethane links. Inother embodiments, the prepolymer is mixed with a triol or higherfunctional polyol and catalyst. In the case where polymer is used, thepolymer is dissolved in solvent or melted and poured on a glass surface.

Example 7: Composite Mesh

In this embodiment a mesh is coupled with a film. The mesh may be aconventional mesh or an absorbable mesh of EXAMPLE 5. The film may be aconventional anti-adhesion film, or a film of EXAMPLE 6. The mesh andfilm are coupled by clipping the mesh in a prepolymer of EXAMPLE 3. Thefilm and coated mesh are brought into physical contact, optionally underpressure, such that as the prepolymer coating polymerizes, it links filmto mesh. Multiple combinations of mesh and film are anticipated.

Example 8: Sheets of Hyaluronic acid/polyurethane (HA-PU) for In VivoStudies

A triol (Multranol 9199) comprised of a copolymer of ethylene oxide andpropylene oxide was obtained from Bayer HealthCare, Tarrytown, N.Y. Into a sealed, heated reactor was placed 455 g (0.1 moles) of Multranol.The Multranol was heated to 85° C. while stirring, and a vacuum appliedto the reaction volume. This was continued until the water content ofthe Multranol was less than 300 ppm. The water content was measuredusing a standard Karl-Fischer setup. To the Multranol was added 52.2 g(0.3 moles.) of toluene diisocyanate (Sigma-Aldrich) in 10 g incrementstaking care to monitor any exothermic raise in temperature, and delayingadditional additions until the temperature of the reaction volumeremained constant (within 1° C.) for 5 minutes. While stirring, thetemperature of the reaction volume was raised at 4° C. per minute untila temperature of 75° C. The reaction was continued until the % NCO was2.5%. To this product, 40 g Hyaluronan of approximately 40,000 Daltonmolecular weight (0.001 moles, Purity Products) was added in solution of500 ml tetrahydrofuran (Sigma-Aldrich). The mixture was stirred untilthe hyaluronan was dissolved. The hyaluronan solution was added in 10 mlincrements to the heated prepolymer volume (above). The head space ofthe reactor was filled with flowing nitrogen to take up thetetrahydrofuran that flashes off as the hyaluronan solution is added.Once the entire volume of the hyaluronan solution is added to theprepolymer, the mixture is heated for an additional 12 hours.Subsequently, a vacuum is applied to the reaction product while stirringand heating until all the volatiles in the reaction volume are removed.The above hyaluronan-polyurethane prepolymer can be mixed with water toform a polymerizing volume which can be cast in sheets. The weight ratioof water to prepolymer can be 50:50 to about 95:5.

Example 9

In this example, the in vivo performance of a surgical barrier layer(HA-PU sheets) comprised of a 75:25 ratio of water to prepolymer ofExample 8 was tested. The tissue response to these HA-PU sheets wascompared to polypropylene mesh. Cells of interest in the study offoreign body response were identified with Trichrome staining, and withH & E staining. Rats were used in assessing differences in foreign bodyresponse. Rats respond to foreign bodies with an exaggerated walling offresponse, so their fibrogenic response is elevated compared to humans.One difficulty in working with rats is their propensity to reopenwounds, infecting the wound site, and compromising a healthy foreignbody response with infection. For this reason it is important to placethe test article dorsally. Coated mesh constructs tend to curl whenhydrated. This morphological change can induce a foreign body response,form gaps in the implantation site which additionally tends to fill inwith fibrotic material. Therefore, it is important to well-localize theimplant, minimize its size, and implant as deeply as practical. Dorsalimplantation was applied left and right, of 2 one centimeter square testarticles to be localized with four sutures placed at the corners.Ideally the test articles are hydrated in saline before implantation. Itis important that the surgical incision be closed with care to avoidreopening. It is important that left and right pockets not becommunicating. It is important that any chemicals used to sterilize thesite, such as butadiene, not come in contact with the test article,since the proposed test articles will take up chemicals readily andthese chemicals will change their foreign body response profile.

In Summary:

10, 1×1 cm uncoated mesh, packaged individually, sterilized

10, 1×1 cm films, packaged individually, sterilized at MAST

10 rats, each to receive 1 mesh and 1 film.

Implanted dorsally, left and right

Harvested at 7 days, placed in formalin

Stained Trichrome

Results:

Numerical values of counts normalized, N=10.

Mesh Vs HA-PU Sheet

Uncoated Mesh HA-PU Sheet Significance Fibrosis [mm] 0.21 ± .07 0.015 ±0.009 P < 0.001 Giant Cells 1.53 ± 0.39  0.01 ± 0.005 P < 0.005Eosinophils 1.99 ± 0.51  0.09 ± 0.02 P < 0.0001 PMNs 0.81 ± 0.24  0.19 ±0.05 P < 0.01 Histiocytes 2.53 ± 0.81  0.55 ± 0.17 P < 0.0005Lymphocytes 1.63 ± 0.41  0.10 ± 0.01 P < 0.01

Example 10: Absorbable Pre-Polymer of Hyaluronan and Polyurethane

A linear, absorbable diol was synthesized. The chemical used in thisexample were obtained from Science Lab. Synthesis comprised 4 g ofTerathane 2000 and 4 g of polycaprolactone diol (Mn=2000) placed into a3-neck-flask. Toluene was added and then a part of the toluene wasremoved by distillation to get a 20% solution. After cooling to roomtemperature 4.05 g of isophorone diisocyanate were added under nitrogen.0.37 g of DBTL (Dibutyltin dilaurate) was added and the mixture washeated to 75° C. After 5 hours 1.28 g of 1,4-butane diol were added andthe reaction mixture was diluted with toluene to get concentration ofall components of 15%. The temperature was raised to 80° C. After 10hours the mixture was allowed to cool to room temperature. The resultingpolymer is precipitated in pentane and dried in vacuo. The mechanicalcharacteristics are:

Elongation at break: 990% Tensile strength: 21 MPa

Degradation: The material was subjected to an accelerated hydrolyticdegradation experiment (2N caustic soda solution at 70° C.). After 4days the molecular weight was reduced from 200 kDa to 19 kDa and theshape of the samples had changed. The material was so week that amechanical characterization was not possible.

In to a sealed, heated reactor was placed 569 g (0.01 moles) of theabove linear polymer with 500 ml acetone. The volume was mixed until thesolid polymer was completely dissolved. To the above mixture was added5.2 g (0.03 moles.) of toluene diisocyanate (Sigma-Aldrich) in 1 gincrements taking care to monitor any exothermic raise in temperature,and delaying additional additions until the temperature of the reactionvolume remained constant (within 1° C.) for 5 minutes. While stirring,the temperature of the reaction volume was raised at 4° C. per minuteuntil a temperature of 75° C. The reaction was continued for 8 hours. Tothis product, 4.0 g Hyaluronan of approximately 40,000 Dalton molecularweight (0.0001 moles, Purity Products) was added in solution of 500 mltetrahydrofuran (Sigma-Aldrich). The mixture was stirred until thehyaluronan was dissolved.

The hyaluronan solution was added in 10 ml increments to the heatedprepolymer volume (above). The head space of the reactor was filled withflowing nitrogen to take up the tetrahydrofuran that flashes off as thehyaluronan solution is added. Once the entire volume of the hyaluronansolution is added to the prepolymer, the mixture is heated for anadditional 12 hours. Subsequently, a vacuum is applied to the reactionproduct while stirring and heating until all the volatiles in thereaction volume are removed. Acetone is added to maintain a mixablevolume. The resulting polymer can be solution cast on glass plate,allowing the acetone to evaporate.

All references cited in this specification, including withoutlimitation, all papers, publications, patents, patent applications,presentations, texts, reports, manuscripts, brochures, books, internetpostings, journal articles, periodicals, and the like, are herebyincorporated by reference into this specification in their entireties.The discussion of the references herein is intended merely to summarizethe assertions made by their authors and no admission is made that anyreference constitutes prior art. Applicants reserve the right tochallenge the accuracy and pertinence of the cited references.

Although embodiments of the disclosure have been described usingspecific terms, devices, and methods, such description is forillustrative purposes only. The words used are words of descriptionrather than of limitation. It is to be understood that changes andvariations may be made by those of ordinary skill in the art withoutdeparting from the spirit or the scope of the present disclosure, whichis set forth in the following claims. In addition, it should beunderstood that aspects of the various embodiments may be interchangedin whole or in part. For example, while methods for the production of acommercially sterile liquid nutritional supplement made according tothose methods have been exemplified, other uses are contemplated.Therefore, the spirit and scope of the appended claims should not belimited to the description of the versions contained therein.

What is claimed is:
 1. A composition comprising a polymerization productof a prepolymer and a linker, wherein the prepolymer is represented byI[BABBAB]_(n)I, wherein, independently for each occurrence, A representsa glycosaminoglycan block, or a salt thereof, each occurrence of Brepresents a single urethane or urea linkage derived from the reactionof a free hydroxy group of a glycosaminoglycan molecule, or a saltthereof, of the glycosarninoglycan block, with an isocyanate group of analiphatic diisocyanate molecule, such that BB is formed from thereaction of both isocyanate groups on a single aliphatic diisocyanatemolecule, I represents an unreacted isocyanate from an aliphaticdiisocyanate, and n represents an integer ranging from 1 to 10,000,wherein the linker comprises the structure ECE, wherein, independentlyfor each occurrence, C represents an ether-ester copolymer block, theether-ester copolymer block including a urethane linkage, wherein theether-ester copolymer block is derived from the product of a polyetherconnected to a polyester via a diisocyanate and E represents the chainextender comprising a terminal hydroxyl, thiol, or amino group, whereinthe terminal hydroxyl, thiol, or amino groups react with the unreactedisocyanates of the prepolymer to produce the polymerization product. 2.The composition of claim 1, wherein the polymerization product comprisesat least one segment represented by [BABBAB]IBCB[BABBAB]n.
 3. Thecomposition of claim 2, wherein the polymerization product furthercomprises at least one isocyanate group.
 4. The composition of claim 1,wherein the polymerization product comprises at least one segmentrepresented by ABBCBBA.
 5. The composition of claim 1, wherein thepolymerization product comprises cross-links formed by the reaction ofmore than two diisocyanate molecules with more than two hydroxyl groupson the glycosaminoglycan block, or salt thereof.
 6. The composition ofclaim 1, wherein the polyether comprises ethylene oxide and propyleneoxide monomers.
 7. The composition of claim 6, wherein the number ratioof ethylene oxide monomers to propylene oxide monomers ranges from about65:35 to about 85:15.
 8. The composition of claim 6, wherein the numberratio of ethylene oxide monomers to propylene oxide monomers ranges fromabout 35:65 to about 15:85 ethylene oxide:propylene oxide.
 9. Thecomposition of claim 7, wherein the hyaluronic acid block and ether havea weight ratio ranging from about 85:15 to about 65:35.
 10. Thecomposition of claim 8, wherein the hyaluronic acid block and ether havea weight ratio ranging from about 35:65 to about 15:85.
 11. Thecomposition of claim 1, wherein the polyester comprises a hydroxyacid.12. A medical device comprising a composition comprising the compositionof claim
 1. 13. The medical device of claim 12, wherein the device is amesh comprising the composition.
 14. The medical device of claim 12,wherein the device is a mesh coated with the composition.
 15. Themedical device of claim 13, wherein the mesh comprises fibers comprisingthe composition.
 16. The medical device of claim 13, wherein the mesh iscoupled to an anti-adhesive film.
 17. The medical device of claim 12,wherein the device is an implantable medical device coated with thecomposition.
 18. The medical device of claim 12, wherein the device is afilm comprising the composition.
 19. The medical device of claim 12,wherein the device is a composite film comprising an anti-adhesion filmcoupled to a film comprising the composition.
 20. A method for reducingprotein adsorption to a medical device in vivo, comprising providing amedical device comprising the composition of claim 1.